Melanoma and other cancers continue to cause significant morbidity and mortality. Having discovered an immune regulator (DC-HIL) whose function can be manipulated to treat cancers, we will: (1) determine whether DC-HIL accounts for resistance to current cancer immunotherapy; (2) characterize the combination of mAb against immune targets that produces optimal treatment benefits; and (3) elucidate how blocking the DC-HIL ligand (syndecan-4) on T cells leads to better outcomes for cancer treatments. Our results will improve current management of metastatic melanoma and other cancers.